Mehcanisms by Which Parenchymal Flow of Cerebrospinal Fluid Regulates Influx and Efflux in the Glymphatic System

The glymphatic system is a brain-wide clearance pathway in which cerebrospinal fluid (CSF) enters along periarterial spaces, exchanges with interstitial fluid in the parenchyma, and exits along perivenous spaces. Dysfunction of this system has been linked to diseases such as Alzheimer’s. While osmotic pressure has been proposed as the driver of CSF influx and efflux across perivascular membranes, the underlying mechanisms remain debated. Here, we demonstrate that pressure gradients generated within the parenchymal compartment can regulate trans-parenchymal CSF transport and drive directional flow across perivascular boundaries. Using high-resolution electron microscopy images, we reconstruct realistic three-dimensional extracellular geometries of brain tissue and perform multiphysics simulations of CSF flow through these porous microenvironments. A parametric study incorporating physiological properties of brain tissue in different states reveals that sleep-associated conditions produce larger pressure gradients across periarterial and perivenous boundaries. This finding aligns with observations of enhanced glymphatic transport during sleep and suggests that parenchymal flow plays an active role in modulating global glymphatic dynamics. Our results provide new insight into how microscale interstitial transport can drive CSF influx and efflux, advancing mechanistic understanding and modeling of brain clearance pathways relevant to neurodegenerative disease research.